RESUMO
Cerebrospinal fluid (CSF) analysis supports diagnosis of neurodegenerative diseases (NDs), however a number of issues limits its potentialities in clinical practice. Here, a newly developed technique for fluid voltammetry, relying on a simple sensor (BIOsensor-based multisensorial system for mimicking Nose, Tongue and Eyes, BIONOTE), was used to test the applicability for CSF analysis. BIONOTE was initially calibrated on an artificial CSF-like solution and then applied on human CSF, either immediately after collection or after refrigerated storage. Following optimization, it was used to evaluate 11 CSF samples correlating the electrochemical dataset with CSF routine parameters and biomarkers of neurodegeneration. Multivariate data analysis was performed for model elaboration and calibration using principal component analysis and partial least squares discriminant analysis. BIONOTE presented a high capacity to predict both physiological and pathological constituents of artificial CSF. It differentiated distinct fresh human CSF samples well but lost accuracy after refrigerated storage. The electrochemical analysis-derived data correlated with either CSF routine cytochemical indexes or a biomarker of neurodegeneration. BIONOTE resulted as being a reliable system for electrochemical analysis of CSF. The CSF fingerprint provided by the sensor has shown itself to be sensitive to CSF modification, thus it is potentially representative of CSF alteration. This result opens the way to its testing in further study addressed at assessing the clinical relevance of the methodology. Because of its advantages due to the ease and rapidity of the methodology, a validation study is now required to translate the technique into clinical practice and improve diagnostic workup of NDs.
Assuntos
Técnicas Biossensoriais , Doenças Neurodegenerativas , Biomarcadores , Análise Discriminante , HumanosRESUMO
TG2576 mice show highest levels of the full length mutant Swedish Human Amyloid Precursor Protein (APPKM670/671LN) during prodromal and early sympotomatic stages. Interestingly, this occurs in association with the unbalanced expression of two of its RNA Binding proteins (RBPs) opposite regulators, the Fragile-X Mental Retardation Protein (FMRP) and the heteronuclear Ribonucleoprotein C (hnRNP C). Whether an augmentation in overall translational efficiency also contributes to the elevation of APP levels at those early developmental stages is currently unknown. We investigated this possibility by performing a longitudinal polyribosome profiling analysis of APP mRNA and protein in total hippocampal extracts from Tg2576 mice. Results showed that protein polysomal signals were exclusively detected in pre-symptomatic (1 months) and early symptomatic (3 months) mutant mice. Differently, hAPP mRNA polysomal signals were detected at any age, but a peak of expression was found when mice were 3-month old. Consistent with an early but transient rise of translational efficiency, the phosphorylated form of the initial translation factor eIF2α (p-eIF2α) was reduced at pre-symptomatic and early symptomatic stages, whereas it was increased at the fully symptomatic stage. Pharmacological downregulation of overall translation in early symptomatic mutants was then found to reduce hippocampal levels of full length APP, Aßspecies, BACE1 and Caspase-3, to rescue predominant LTD at hippocampal synapses, to revert dendritic spine loss and memory alterations, and to reinstate memory-induced c-fosactivation. Altogether, our findings demonstrate that overall translation is upregulated in prodromal and early symptomatic Tg2576 mice, and that restoring proper translational control at the onset of AD-like symptoms blocks the emergence of the AD-like phenotype.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Sintomas Prodrômicos , Regulação para Cima , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Animais , Modelos Animais de Doenças , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Proteína do X Frágil da Deficiência Intelectual , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Sinapses/metabolismoRESUMO
The functional loop involving the ventral tegmental area (VTA), dorsal hippocampus and nucleus accumbens (NAc) plays a pivotal role in the formation of spatial memory and persistent memory traces. In particular, the dopaminergic innervation from the VTA to the hippocampus is critical for hippocampal-related memory function and alterations in the midbrain dopaminergic system are frequently reported in Alzheimer's disease (AD), contributing to age-related decline in memory and non-cognitive functions. However, much less is known about the hippocampus-NAc connectivity in AD. Here, we evaluated the functioning of the hippocampus-to-NAc core connectivity in the Tg2576 mouse model of AD that shows a selective and progressive degeneration of VTA dopaminergic neurons. We show that reduced dopaminergic innervation in the Tg2576 hippocampus results in reduced synaptic plasticity and excitability of dorsal subiculum pyramidal neurons. Importantly, the glutamatergic transmission from the hippocampus to the NAc core is also impaired. Chemogenetic depolarisation of Tg2576 subicular pyramidal neurons with an excitatory Designer Receptor Exclusively Activated by Designer Drugs, or systemic administration of the DA precursor levodopa, can both rescue the deficits in Tg2576 mice. Our data suggest that the dopaminergic signalling in the hippocampus is essential for the proper functioning of the hippocampus-NAc excitatory synaptic transmission.
Assuntos
Doença de Alzheimer/metabolismo , Dopamina/metabolismo , Hipocampo/metabolismo , Núcleo Accumbens/metabolismo , Transmissão Sináptica/fisiologia , Doença de Alzheimer/genética , Animais , Dopamina/genética , Neurônios Dopaminérgicos/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Técnicas de Cultura de ÓrgãosRESUMO
OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease whose pathophysiological deficits, causing impairment in motor function, are largely unknown. Here we propose that hydrogen sulfide (H2 S), as a glial-released inflammatory factor, contributes to ALS-mediated motor neuron death. METHODS: H2 S concentrations were analyzed in the cerebrospinal fluid of 37 sporadic ALS patients and 14 age- and gender-matched controls, in tissues of a familial ALS (fALS) mouse model, and in spinal cord culture media by means of a specific and innovative high-performance liquid chromatography method. The effects of H2 S on motor neurons cultures was analyzed immunohistochemically and by patch clamp recordings and microfluorometry. RESULTS: We found a significantly high level of H2 S in the spinal fluid of the ALS patients. Consistently, we found increased levels of H2 S in the tissues and in the media from mice spinal cord cultures bearing the fALS mutation SOD1G93A. In addition, NaHS, an H2 S donor, added to spinal culture, obtained from control C57BL/6J mice, is toxic for motor neurons, and induces an intracellular Ca(2+) increase, attenuated by the intracytoplasmatic application of adenosine triphosphate. We further show that H2 S is mainly released by astrocytes and microglia. INTERPRETATION: This study unravels H2 S as an astroglial mediator of motor neuron damage possibly involved in the cellular death characterizing ALS.
Assuntos
Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/diagnóstico , Sulfeto de Hidrogênio/líquido cefalorraquidiano , Idoso , Animais , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Medula Espinal/metabolismoRESUMO
STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and low bone mineral density (BMD) are 2 prevalent conditions with a significant negative impact on patients' well-being and quality of life. Recent research has shown low BMD at different bone sites in male patients with OSA. Although the efficacy of continuous positive airway pressure (CPAP) treatment for OSA has been widely demonstrated, the evidence for understanding its impact on BMD and other bone-related outcomes is insufficient. The aim of this observational study was to investigate the effect of 12 months of CPAP treatment on lumbar and femur BMD and bone-related serum biomarkers in male patients with severe OSA. METHODS: Sixty patients (mean age: 55.1 ± 9.9 years) were consecutively included and underwent BMD measurement with dual-energy x-ray absorptiometry at baseline and after 12 months of CPAP treatment. Vitamin D, parathyroid hormone, and calcium serum levels were examined at the same time points. RESULTS: A significant increase in BMD in the L1 (P < .001, d = 0.27) and L2 (P < .001, d = 0.26) vertebrae was observed after CPAP treatment, along with an increase in vitamin D (P < .001, d = 0.71) and calcium (P < .001, d = 0.73) levels and a decrease in parathyroid hormone levels (P < .001, d = 0.60). The increase in BMD in L1 was significantly correlated with the decrease in parathyroid hormone serum levels (r = -.50, P < .001). CONCLUSIONS: Overall, these findings showed that beneficial OSA treatment might restore bone health and support CPAP treatment as a feasible strategy to improve BMD in male patients with severe OSA. Accordingly, diagnosing and targeting OSA may be warranted in the treatment of male patients with undetermined osteopenia and osteoporosis. CITATION: Carpi M, Cordella A, Placidi F, et al. Continuous positive airway pressure treatment improves bone mineral density in men affected by severe obstructive sleep apnea syndrome. J Clin Sleep Med. 2024;20(1):67-73.
Assuntos
Densidade Óssea , Apneia Obstrutiva do Sono , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Cálcio , Pressão Positiva Contínua nas Vias Aéreas , Qualidade de Vida , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/terapia , Síndrome , Vitamina D , Hormônio ParatireóideoAssuntos
Densidade Óssea , Doenças Ósseas Metabólicas/epidemiologia , Osteoporose/epidemiologia , Apneia Obstrutiva do Sono/complicações , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Fêmur/diagnóstico por imagem , Humanos , Vértebras Lombares/diagnóstico por imagem , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Neurotensin (NT) is a 13-amino acid peptide acting as a neuromodulator in the CNS. NT immunoreactive cell bodies, synaptic terminals and receptors (NTS) are intimately associated with the dopaminergic system. In fact, NT exerts a stimulatory action on the dopaminergic (DAergic) neurons of substantia nigra pars compacta (SNpc) and ventral tegmental area by activating a mixed cation conductance, reducing D2-autoinhibition and modulating NMDA and AMPA transmission. In the present work, we describe an inhibitory effect of NT on metabotropic glutamate receptor I (mGluR I) actions in rat SNpc DAergic neurons. NTS and mGluR I share the same Gαq/11-PLC-IP3-Ca2+ intracellular pathway which causes either activation of unspecific cationic conductance or intracellular Ca2+ accumulation. We find that NT inhibits both inward current and the associated intracellular calcium elevation, elicited by the selective mGluR I agonist S-DHPG, in a concentration-dependent manner. This effect is mediated by type 1/2 NT receptors (NTS1/2), as revealed by pharmacological analysis. Activation of other metabotropic receptors, such as muscarinic and GABAB, does not inhibit mGluR I inward currents. PKC, MEK 1-2, calcineurin, clathrin-dependent endocytosis and intracellular Ca2+ elevation are not involved in the NT-mediated modulation of mGluR I responses. Interestingly, inhibition of G-protein coupled receptor kinases (GRKs) 2/3 exacerbates the NT-induced mGluR I inhibition while sustaining the NT-induced inward current during repeated agonist stimulation. These data suggest that GRKs are key molecules regulating either the NT excitation or the cross-talk between NTS1/2 and mGluR I in DAergic neurons of rat midbrain by tuning the degree of NTS1/2 desensitization.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Quinases de Receptores Acoplados a Proteína G/metabolismo , Neurotensina/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Neurotensina/metabolismo , Substância Negra/metabolismo , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Substância Negra/efeitos dos fármacosRESUMO
BACKGROUND: Obstructive Sleep Apnea (OSA) is associated with pathological changes of cerebral ß-amyloid dynamics. Orexin has been demonstrated interfering with ß-amyloid metabolism in Alzheimer's Disease (AD) pathology. The present study investigated cerebrospinal-fluid (CSF) ß-amyloid40 (Aß40), ß-amyloid42 (Aß42) and orexin levels in OSA patients compared to AD patients and controls. METHODS: OSA and AD patients were included in this study and compared to a group of controls. Patients and controls underwent lumbar puncture for the assessment of CSF Aß40, Aß42, tau proteins, orexin levels, and polysomnography to measure nocturnal sleep architecture. RESULTS: 20 OSA patients, 20 AD patients, and 15 controls were included in our study. OSA patients showed higher CSF orexin levels than AD patients and controls, and AD patients showed higher CSF orexin levels than controls. Moreover, CSF Aß40 and Aß42 were lower in OSA patients than controls, but higher in OSA patients compared to AD patients. However, AD patients showed lower CSF Aß42 levels but comparable CSF Aß40 levels than controls. Sleep macrostructure was similarly altered in OSA and AD patients compared to controls. Finally, the apnea-hypopnea index (AHI) was related to the ratio Aß42/Aß40 and CSF orexin levels in OSA patients. CONCLUSION: This study proved the alteration of CSF orexin levels and ß-amyloid isoforms 40 and 42 in OSA patients. We suppose that sleep disruption and intermittent hypoxia, the two core features of OSA, may induce orexinergic system and cerebral ß-amyloid metabolism dysregulation. This evidence further supports the current hypothesis that OSA may possibly start AD neuropathological processes.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Orexinas/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Apneia Obstrutiva do Sono/líquido cefalorraquidiano , Apneia Obstrutiva do Sono/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Neuroinflammation is one of the hallmarks of Parkinson's disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD - to modulate disease progression - still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.
Assuntos
Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/administração & dosagem , Inflamação/prevenção & controle , Degeneração Neural/prevenção & controle , Doença de Parkinson/prevenção & controle , Animais , Ácidos Docosa-Hexaenoicos/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Imbalances between excitatory and inhibitory synaptic transmission cause brain network dysfunction and are central to the pathogenesis of neurodevelopmental disorders. Parvalbumin interneurons are highly implicated in this imbalance. Here, we probed the social behavior and hippocampal function of mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene crucial for brain development. We show that heterozygous Ambra1 mice (Ambra+/-) are characterized by loss of hippocampal parvalbumin interneurons, decreases in the inhibition/excitation ratio, and altered social behaviors that are solely restricted to the female gender. Loss of parvalbumin interneurons in Ambra1+/- females is further linked to reductions of the inhibitory drive onto principal neurons and alterations in network oscillatory activity, CA1 synaptic plasticity, and pyramidal neuron spine density. Parvalbumin interneuron loss is underlined by increased apoptosis during the embryonic development of progenitor neurons in the medial ganglionic eminence. Together, these findings identify an Ambra1-dependent mechanism that drives inhibition/excitation imbalance in the hippocampus, contributing to abnormal brain activity reminiscent of neurodevelopmental disorders.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Inibição Neural , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/fisiopatologia , Animais , Apoptose , Comportamento Animal , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Ritmo Gama , Interneurônios/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/patologia , Plasticidade Neuronal , Parvalbuminas/metabolismo , Comportamento SocialRESUMO
Complement system dysregulation has been hypothesized as a possible pathogenetic factor triggering epileptogenesis in both animal models and human studies. The aim of the present study is to evaluate the complement system in adult patients affected by idiopathic generalized epilepsy (IGE), either untreated or treated by antiepileptic drugs (AEDs). Thirty-seven IGE patients were compared to a population of 20 matched healthy controls. IGE patients underwent neurological investigation, epilepsy diary, 24-h EEG recording, and blood sample for the assessment of the complement factors C3 and C4, fibrinogen, and C-reactive protein (CRP) serum levels. We excluded patients with clinical and subclinical seizures in the 24h before obtaining the blood sample. We observed decreased C3 and C4 serum levels in IGE patients with respect to controls (p<0.05), and in untreated compared to treated IGE patients (p<0.05). We found significant correlations in the IGE group linking C3 to C4 (R=0.34), CRP (R=0.49), and fibrinogen serum levels (R=0.61). This study proved a significant alteration of the complement system in IGE patients not related to ictal conditions. The hyperactivation of the complement cascade was more significant in untreated than in treated IGE patients. Hence, this study documented the complement factors dysregulation in patients affected by IGE. However, the impact of complement system alteration in the epileptogenetic process needs to be clarified.
Assuntos
Anticonvulsivantes/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/fisiopatologia , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Eletroencefalografia , Feminino , Fibrinogênio/metabolismo , Humanos , Masculino , Adulto JovemRESUMO
Study Objectives: Obstructive sleep apnea (OSA) is a common sleep disorder. The, literature lacks studies examining sleep, cognition, and Alzheimer's Disease (AD) cerebrospinal fluid (CSF) biomarkers in OSA patients. Therefore, we first studied cognitive performances, polysomnographic sleep, and CSF ß-amyloid42, tau proteins, and lactate levels in patients affected by subjective cognitive impairment (SCI) divided in three groups: OSA patients (showing an Apnea-Hypopnea Index [AHI] ≥15/hr), controls (showing an AHI < 15/hr), and patients with OSA treated by continuous positive airway pressure (CPAP). Methods: We compared results among 25 OSA, 10 OSA-CPAP, and 15 controls who underwent a protocol counting neuropsychological testing in the morning, 48-hr polysomnography followed by CSF analysis. Results: OSA patients showed lower CSF Aß42 concentrations, higher CSF lactate levels, and higher t-tau/Aß42 ratio compared to controls and OSA-CPAP patients. OSA patients also showed reduced sleep quality and continuity and lower performances at memory, intelligence, and executive tests than controls and OSA-CPAP patients. We found significant relationships among higher CSF tau proteins levels, sleep impairment, and increased CSF lactate levels in the OSA group. Moreover, lower CSF Aß42 levels correlate with memory impairment and nocturnal oxygen saturation parameters in OSA patients. Conclusions: We hypothesize that OSA reducing sleep quality and producing intermittent hypoxia lowers CSF Aß42 levels, increases CSF lactate levels, and alters cognitive performances in SCI patients, thus inducing early AD clinical and neuropathological biomarkers changes. Notably, controls as well as OSA-CPAP SCI patients did not show clinical and biochemical AD markers. Therefore, OSA may induce early but possibly CPAP-modifiable AD biomarkers changes.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Biomarcadores/líquido cefalorraquidiano , Pressão Positiva Contínua nas Vias Aéreas , Intervenção Médica Precoce , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/terapia , Idoso , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Cognição , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/complicações , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/terapia , Diagnóstico Precoce , Feminino , Humanos , Inteligência , Ácido Láctico/líquido cefalorraquidiano , Masculino , Memória , Transtornos da Memória/líquido cefalorraquidiano , Transtornos da Memória/complicações , Transtornos da Memória/prevenção & controle , Transtornos da Memória/terapia , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Polissonografia , Sono , Apneia Obstrutiva do Sono/líquido cefalorraquidiano , Apneia Obstrutiva do Sono/fisiopatologia , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVE: The aim of this study was to evaluate the effect of one-year useful continuous positive airway pressure (CPAP) treatment on serum vitamin D levels in middle-aged men affected by obstructive sleep apnea syndrome (OSAS). METHODS: This is a secondary investigation related to a previously published observational study about the effect of short-term CPAP therapy on serum vitamin D levels in severe OSAS (Apnea-Hypopnea Index - AHI- >30/h) patients. In the present study, we included patients participating to the previous investigation who repeated serum vitamin D assessment after one year of useful CPAP treatment, and compared to control a group of OSAS patients with scarce compliance to CPAP treatment. OSAS patients with beneficial use of CPAP treatment were distributed in obese (Body Mass Index - BMI ≥30) and non-obese (BMI < 30). Moreover, the mean change between baseline and one-year follow-up (Δ) of serum vitamin D levels was correlated with demographic, polygraphic and clinical data throughout a multiple regression analysis. RESULTS: We documented the significant increase of serum vitamin D levels after one year of CPAP treatment in the OSAS group (n = 39, p < 0.001) and in both subgroups of obese (n = 23, p < 0.01) and non-obese (n = 16, p < 0.01) OSAS patients. Conversely, OSAS patients with a scarce compliance to CPAP therapy did not change serum vitamin D levels after one year (n = 10, p > 0.05). OSAS patients with beneficial CPAP treatment showed higher vitamin D serum levels after one year and a more frequent shift from insufficient to sufficient vitamin D status compared to OSAS patients not adequately using CPAP treatment. In particular, the obese OSAS patients subgroup shifted from insufficient (≤20 ng/mL) to sufficient (>20 ng/mL) vitamin D status after CPAP therapy more than the non-obese OSAS patients subgroup (p < 0.05). We observed higher Δ of vitamin D serum levels, Epworth Sleepiness Scale score, and AHI in obese compared to non-obese OSAS patients. Finally, BMI obtained at baseline positively correlated with Δ of vitamin D serum levels. DISCUSSION: This study documented that long-term CPAP treatment is a viable therapeutic choice for correcting both sleep apnea condition and vitamin D deficiency in middle-aged male OSAS patients. Significantly, this effect was more evident in obese subjects and possibly represents a valid therapeutic strategy to ensure sufficient vitamin D levels in these patients, which frequently show a deficient vitamin D status.
Assuntos
Assistência de Longa Duração , Obesidade/complicações , Cooperação do Paciente , Síndromes da Apneia do Sono/complicações , Vitamina D/sangue , Pressão Positiva Contínua nas Vias Aéreas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Síndromes da Apneia do Sono/terapia , Inquéritos e Questionários , Deficiência de Vitamina D/sangueRESUMO
The presence of α-synuclein (α-syn) in Lewy bodies and Lewy neurites is an important characteristic of the neurodegenerative processes of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons in Parkinson's disease (PD) and other synucleinopathies. Here we report that Berlin-Druckrey rats carrying a spontaneous mutation in the 3' untranslated region of α-syn mRNA (m/m rats) display a marked accumulation of α-syn in the mesencephalic area, striatum and frontal cortex, accompanied to severe dysfunctions in the dorsolateral striatum. Despite a small reduction in the number of SNpc and ventral tegmental area DAergic cells, the surviving dopaminergic neurons of the m/m rats do not show clear-cut alterations of the spontaneous and evoked firing activity, DA responses and somatic amphetamine-induced firing inhibition. Interestingly, mutant DAergic neurons display diminished whole-cell Ih conductance and a reduced frequency of spontaneous excitatory synaptic currents. By contrast, m/m rats show a severe impairment of DA and glutamate release in the dorsolateral striatum, as revealed by amperometric measure of DA currents and by electrophysiological recordings of glutamatergic synaptic events in striatal medium spiny neurons. These functional impairments are paralleled by a decreased expression of the DA transporter and VGluT1 proteins in the same area. Thus, together with α-syn overload in the mesencephalic region, striatum and frontal cortex, the main functional alterations occur in the DAergic and glutamatergic terminals in the dorsal striatum of the m/m rats.
Assuntos
Neurônios Dopaminérgicos/fisiologia , Ácido Glutâmico/metabolismo , Potenciais da Membrana/fisiologia , Mesencéfalo/citologia , alfa-Sinucleína/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Animais Recém-Nascidos , Bicuculina/farmacologia , Contagem de Células , Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Ratos , Potenciais Sinápticos/efeitos dos fármacos , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , alfa-Sinucleína/genéticaRESUMO
Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer's disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing.
Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Neurônios Dopaminérgicos/patologia , Memória , Recompensa , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Di-Hidroxifenilalanina/farmacologia , Di-Hidroxifenilalanina/uso terapêutico , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Alimentos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/complicações , Inflamação/patologia , Camundongos Transgênicos , Degeneração Neural/complicações , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Plasticidade Neuronal/efeitos dos fármacos , Núcleo Accumbens/patologia , Núcleo Accumbens/fisiopatologia , Placa Amiloide/complicações , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia , Selegilina/farmacologia , Selegilina/uso terapêutico , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/patologia , Área Tegmentar Ventral/fisiopatologiaRESUMO
Dopamine neurons in the substantia nigra pars compacta regulate not only motor but also cognitive functions. NMDA receptors play a crucial role in modulating the activity of these cells. Considering that the amino-acid D-Aspartate has been recently shown to be an endogenous NMDA receptor agonist, the aim of the present study was to examine the effects of D-Aspartate on the functional properties of nigral dopamine neurons. We compared the electrophysiological actions of D-Aspartate in control and D-aspartate oxidase gene (Ddo(-/-)) knock-out mice that show a concomitant increase in brain D-Aspartate levels, improved synaptic plasticity and cognition. Finally, we analyzed the effects of L-Aspartate, a known dopamine neuron endogenous agonist in control and Ddo(-/-) mice. We show that D- and L-Aspartate excite dopamine neurons by activating NMDA, AMPA and metabotropic glutamate receptors. Ddo deletion did not alter the intrinsic properties or dopamine sensitivity of dopamine neurons. However, NMDA-induced currents were enhanced and membrane levels of the NMDA receptor GluN1 and GluN2A subunits were increased. Inhibition of excitatory amino-acid transporters caused a marked potentiation of D-Aspartate, but not L-Aspartate currents, in Ddo(-/-) neurons. This is the first study to show the actions of D-Aspartate on midbrain dopamine neurons, activating not only NMDA but also non-NMDA receptors. Our data suggest that dopamine neurons, under conditions of high D-Aspartate levels, build a protective uptake mechanism to compensate for increased NMDA receptor numbers and cell hyper-excitation, which could prevent the consequent hyper-dopaminergia in target zones that can lead to neuronal degeneration, motor and cognitive alterations.
Assuntos
Ácido Aspártico/metabolismo , Ácido D-Aspártico/metabolismo , Neurônios Dopaminérgicos/fisiologia , Parte Compacta da Substância Negra/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Ácido Aspártico/administração & dosagem , D-Aspartato Oxidase/genética , Ácido D-Aspártico/administração & dosagem , Dopamina/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parte Compacta da Substância Negra/efeitos dos fármacos , Receptores de AMPA/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Receptores de N-Metil-D-Aspartato/agonistasRESUMO
STUDY OBJECTIVE: Recent studies report a link between obstructive sleep apnea (OSA) syndrome, low vitamin D levels, and high parathyroid hormone (PTH) concentrations. The aim of the current study is to evaluate the effect of 7-night continuous positive airway pressure (CPAP) therapy on serum vitamin D, PTH, and calcium levels in patients with severe OSA syndrome. METHODS: Patients with severe OSA were enrolled into the study and compared to control subjects. Patients with OSA underwent CPAP therapy for 7 nights and were consequently divided into responders (OSA-R, mean residual AHI < 5/h) and nonresponders (OSA-nR, mean residual AHI > 5/h). Serum vitamin D, PTH, and calcium levels were measured at baseline in patients with severe OSA (apnea-hypopnea index > 30/h) and control subjects. Patients with OSA underwent a final morning blood sample after 7-night CPAP therapy. RESULTS: We enrolled 90 patients with OSA into the study (65 OSA-R and 25 OSA-nR) compared to 32 control subjects. At baseline, lower vitamin D and higher PTH levels were detected in the OSA group compared to controls. After 7-night CPAP therapy, male OSA-R patients showed a significant increase in vitamin D levels. Conversely, female OSA-R patients did not show the same increase in vitamin D levels. It was also observed that OSA-nR subjects did not show modifications of serum markers after nCPAP-therapy. CONCLUSIONS: The study demonstrates that short-term nCPAP treatment is able to promote the recovery of vitamin D homeostasis in male patients with OSA. The mediation of sexual hormones in regulating vitamin D is a possible explanation of the lack of recovery of vitamin D homeostasis in female patients with OSA as it often affects postmenopausal women.